CAR macrophages go beyond T cells to fight solid tumors

Chimeric antigen receptor (CAR) T cell therapy has been a game-changer for blood cancers but has faced challenges in targeting solid tumors. Now researchers from the Perelman School of Medicine at the University of Pennsylvania may have an alternative to T cell therapy that can overcome those challenges. Their research shows genetically engineering macrophages - an immune cell that eats invaders in the body - could be the key to unlocking cellular therapies that effectively target solid tumors. The team was able to show these CAR macrophages can kill tumors both in human samples in the lab and in mouse models. They published their proof-of-concept paper in Nature Biotechnology today.

The approach in this study is closely related to CAR T cell therapy, in which patient immune cells are engineered to fight cancer, but it has some key differences. Most importantly, it centers around macrophages, which eat invading cells rather than targeting them for destruction the way T cells do; while T cells are more like a game of Space Invaders, macrophages are like Pac-Man.

Macrophages also have another key difference from T cells in that they are the body's first responders to viral infections. This has historically presented challenges in trying to engineer them to attack cancer, since macrophages are resistant to infection by the standard viral vectors used in gene and cell therapy.

"We have known how to engineer T cells to do this for years, but the fact that macrophages are innately resistant to the viral vectors that we use in our CAR T cells presented a unique challenge, which we show here we were able to overcome," said the study's senior author Saar Gill, MD, PhD, an assistant professor of Hematology-Oncology and a member of Penn's Abramson Cancer Center.

In fact, this anti-viral property carried another unexpected benefit. Macrophages are generally among the first cells to be drawn in by cancer, and they are exploited to help tumors instead of eating them. However, the research team showed that when the viral vector is inserted, not only do these engineered macrophages express the CAR, they also transform into highly inflammatory cells. This transformation allows macrophages to resist being co-opted by tumors.

Researchers say CAR macrophages may also be able to stimulate the rest of the immune system as they attack, potentially opening the door to a greater immune response.

"Finding ways to draw the rest of the body's powerful immune system into the fight would mean an even greater impact than what a cellular therapy can do on its own, so our future research will include efforts to better understand this possibility and how we might be able to exploit it to kill cancer," said the study's first author Michael Klichinsky, PhD, who was a graduate student at Penn while he completed the work. This paper represents the culmination of his graduate career in Gill's lab. Klichinsky and Gill went on to co-found a company, Carisma Therapeutics, based on the CAR Macrophage approach.

Michael Klichinsky, Marco Ruella, Olga Shestova, Xueqing Maggie Lu, Andrew Best, Martha Zeeman, Maggie Schmierer, Konrad Gabrusiewicz, Nicholas R Anderson, Nicholas E Petty, Katherine D Cummins, Feng Shen, Xinhe Shan, Kimberly Veliz, Kristin Blouch, Yumi Yashiro-Ohtani, Saad S Kenderian, Miriam Y Kim, Roddy S O'Connor, Stephen R Wallace, Miroslaw S Kozlowski, Dylan M Marchione, Maksim Shestov, Benjamin A Garcia, Carl H June, Saar Gill.
Human chimeric antigen receptor macrophages for cancer immunotherapy.
Nature Biotechnology, 2020. doi: 10.1038/s41587-020-0462-y.

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